DE69433325T2 - TRANSGENIC ANTIBODY PRODUCTION IN MILK - Google Patents
TRANSGENIC ANTIBODY PRODUCTION IN MILK Download PDFInfo
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- DE69433325T2 DE69433325T2 DE69433325T DE69433325T DE69433325T2 DE 69433325 T2 DE69433325 T2 DE 69433325T2 DE 69433325 T DE69433325 T DE 69433325T DE 69433325 T DE69433325 T DE 69433325T DE 69433325 T2 DE69433325 T2 DE 69433325T2
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New breeds of animals
- A01K67/027—New breeds of vertebrates
- A01K67/0275—Genetically modified vertebrates, e.g. transgenic
- A01K67/0278—Humanized animals, e.g. knockin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/04—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies from milk
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
- C07K16/3046—Stomach, Intestines
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2207/00—Modified animals
- A01K2207/15—Humanized animals
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/105—Murine
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/01—Animal expressing industrially exogenous proteins
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
- Y10S530/867—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof involving immunoglobulin or antibody produced via recombinant dna technology
Abstract
Description
Gebiet der ErfindungTerritory of invention
Diese Erfindung betrifft ein Verfahren zur Herstellung monoklonaler Antikörper in Säugetiermilch, insbesondere durch Erzeugung transgener Tiere, die selektiv Fremdantikörper-Gene in Brustdrüsen- bzw. Milchdrüsenepithelzellen exprimieren.This invention relates to a method for the production of monoclonal antibodies in mammalian milk, in particular by generating transgenic animals that selectively generate foreign antibody genes in mammary glands or mammary epithelial cells express.
Hintergrund der Erfindungbackground the invention
Immunglobuline sind heteropolymere Proteine, die normalerweise von zirkulierenden B-Lymphozyten synthetisiert, modifiziert, zusammengebaut und sezerniert werden. Unter Verwendung der DNA-Rekombinationstechnologie ist es möglich, andere Zellen als B-Lymphozyten so zu programmieren, dass sie Immunglobulingene exprimieren. Die bei dieser Bemühung auftretenden Schwierigkeiten rühren von mehreren Faktoren her: 1) sowohl schwere als auch leichte Ketten von Immunglobulinen müssen in geeigneten Konzentrationen bzw. Niveaus coexprimiert werden; 2) naszierende Immunglobulinpolypeptide machen eine Vielzahl von co- und post-translationalen Modifikationen durch, die in heterologen Zellen nicht mit einer ausreichenden Zuverlässigkeit oder Leistungsfähigkeit eintreten könnten; 3) Immunglobuline benötigen akzessorische Chaperon-Proteine für ihren Zusammenbau; 4) die Synthese- und Sekretionskapazität der Zelle kann zur Sezernierung großer Mengen an heterologen Proteinen ungeeignet sein; 5) die sezernierten Immunglobuline können im extrazellulären Milieu einer Fremdzelle instabil sein.Immunoglobulins are heteropolymeric Proteins normally synthesized by circulating B-lymphocytes, modified, assembled and secreted. Using recombinant DNA technology Is it possible, cells other than B lymphocytes to be programmed to express immunoglobulin genes. The in this effort any difficulties that arise from several factors: 1) both heavy and light chains of immunoglobulins are co-expressed in appropriate concentrations or levels; 2) Nascent immunoglobulin polypeptides make a variety of through co- and post-translational modifications made in heterologous Cells do not have sufficient reliability or performance could occur; 3) Need immunoglobulins accessory chaperone proteins for assembly; 4) the Synthesis and secretion capacity The cell can secrete large amounts of heterologous proteins be unsuitable; 5) the secreted immunoglobulins can in extracellular Environment of a foreign cell be unstable.
Weil Immunglobuline therapeutische, diagnostische und industrielle bzw. gewerbliche Anwendungen aufweisen, besteht ein Bedarf in der Wissenschaft nach Expressionssystemen, bei denen diese Proteine reproduzierbar in einer hohen Konzentration, in einer funktionellen Konfiguration bzw. Aufbau und in einer Form hergestellt werden können, die ermöglicht, dass diese einfach geerntet und aufgereinigt werden können. Die Entwicklung der transgenen Tier-Technologie hat die Möglichkeit der Verwendung großer Tiere als genetisch programmierte Proteinfabriken eröffnet. PCT-Anmeldung WO 90/04036 (veröffentlicht am 19.04.1990) of fenbart die Verwendung der transgenen Technologie zur Immunglobulinexpression. WO 92/03918 (19.03.1992) und WO 93/12227 (24.06.1993) lehren die Einbringung nicht neu angeordneter Immunglobulingene in der Keimbahn transgener Tiere. Die Verwendung intakter Immunglobulingene (einschließlich ihrer jeweiligen Promotorregionen) hat ihre Expression in Lymphozyten und die Sekretion in den Blutstrom des Wirtstieres zur Folge; dies macht eine Strategie zur Unterdrückung der Expression der endogenen Wirtsimmunglobuline notwendig und lässt das Problem entstehen, Immunglobuline aus dem Serum aufzureinigen, das viele andere Proteine enthält, einschließlich proteolytischer Enzyme. Wenn weiterhin der transgene Ansatz gewählt wird, müssen die Gene der schweren und leichten Kette beide in das Wirtsgenom in einer Weise eingebaut werden, die ihre gleichzeitige Expression ermöglicht.Because immunoglobulins are therapeutic, have diagnostic and industrial or commercial applications, there is a need in science for expression systems, where these proteins are reproducible in a high concentration, manufactured in a functional configuration or structure and in one form can be which enables that they can be easily harvested and cleaned up. The development of transgenic animal technology has the possibility of using great Animals opened as genetically programmed protein factories. PCT Application WO 90/04036 (published on April 19, 1990) disclosed the use of transgenic technology for immunoglobulin expression. WO 92/03918 (19.03.1992) and WO 93/12227 (June 24, 1993) teach the introduction of immunoglobulin genes that have not been rearranged in the germline of transgenic animals. The use of intact immunoglobulin genes (including their respective promoter regions) has their expression in lymphocytes and secretion into the bloodstream of the host animal; this makes a strategy of oppression the expression of the endogenous host immunoglobulins necessary and leaves that Problem arise to purify immunoglobulins from the serum, the contains many other proteins including proteolytic enzymes. If the transgenic approach is still chosen, must they Heavy and light chain genes are both in the host genome be built in a way that their simultaneous expression allows.
Eine weitere Option bei der Erzeugung transgener Tiere besteht darin, das interessierende Gen an einen heterologen Transkriptions-Promotor zu binden, der lediglich in einem definierten Zelltyp im Wirt funktioniert. Auf diese Weise kann eine gewebsspezifische Expression des Transgens programmiert werden. US-Patent Nr. 4 873 316 (erteilt am 10. Oktober 1989) offenbart die Produktion von rekombinantem Gewebsplasminogenaktivator (recombinant tissue plaminogen activator = TPA) in der Milch von transgenen Mäusen, bei denen das TPA-Gen an den Promotor des Milchproteins Casein gebunden ist. Andere Promotoren, die in einer ähnlichen Weise exprimiert wurden, schließen zystischen Fibrose-Transmembrankonduktanzregulator (= cystic fibrosis transmembrane conductance regulator) (DiTullio et al., Bio/Technology 10: 74, 1992), Urokinase (Meade et al., Bio/Technology 8: 443, 1990), Interleukin-2 (Buhler et al., Bio/Technology 8: 140, 1990) und den Antihämophilen Faktor IX (Clark et al., Bio/Technology 7: 487, 1989) ein. Bemerkenswerter Weise sind diese Proteine insgesamt einfache Ein-Kettenpolypeptide, die keine Multimerisierung oder Zusammenbau vor der Sekretion erfordern.Another option in generation transgenic animals consists of transferring the gene of interest to one to bind heterologous transcription promoter that is only in a defined cell type in the host works. In this way can program a tissue-specific expression of the transgene become. U.S. Patent No. 4,873,316 (issued October 10, 1989) the production of recombinant tissue plasminogen activator (recombinant tissue plaminogen activator = TPA) in the milk of transgenic mice which the TPA gene bound to the promoter of the milk protein casein is. Other promoters that were expressed in a similar manner conclude cystic fibrosis transmembrane conductance regulator (= cystic fibrosis transmembrane conductance regulator) (DiTullio et al., Bio / Technology 10: 74, 1992), urokinase (Meade et al., Bio / Technology 8: 443, 1990), Interleukin-2 (Buhler et al., Bio / Technology 8: 140, 1990) and the antihemophiles Factor IX (Clark et al., Bio / Technology 7: 487, 1989). remarkable Way these proteins are overall simple single chain polypeptides, that do not require multimerization or assembly prior to secretion.
Es hat sich nunmehr herausgestellt, dass, wenn ein transgenes Säugetier erzeugt wird, das gepaarte Immunglobulin leichte und schwere Ketten-Gene unter der Kontrolle des Casein-Promotors trägt, ein solches Tier große Mengen an zusammengesetzten Immunglobulinen erzeugt, die in ihre Milch sezerniert werden. Unter Verwendung der DNA-Konstrukte gemäß der vorliegenden Erfindung wird eine überraschend hohe Effizienz der Co-Integration von schwere und leichte Ketten-Genen beobachtet. Unter Verwendung des vorliegenden Verfah rens und solcher Konstrukte ist es zum ersten Mal möglich, eine Brustdrüsenpithelzelle so zu programmieren, dass sie komplexe tetramere Glycoproteine erzeugt und zusammenbaut und diese in hohen Mengen sezerniert.It has now been found that when a transgenic mammal is produced, the paired immunoglobulin light and heavy chain genes under the control of the casein promoter wearing, such an animal great Amounts of composite immunoglobulins are produced that are in their Milk to be secreted. Using the DNA constructs according to the present Invention becomes a surprise high efficiency of the co-integration of heavy and light chain genes observed. Using the present method and such Constructs made it possible for the first time to have a mammary glandular epithelial cell to be programmed to generate complex tetrameric glycoproteins and assembles and secretes them in large quantities.
Es ist demgemäß eine Aufgabe der vorliegenden Erfindung, Verfahren zur Produktion von Immunglobulinen in der Milch transgener Säugetiere in großem Maßstab bereitzustellen.It is accordingly an object of the present Invention, process for the production of immunoglobulins in milk transgenic mammals in large scale provide.
Es ist eine weitere Aufgabe der Erfindung, Verfahren zur Entwicklung bzw. zum Design synthetischer Immunglobuline bereitzustellen, die in der Milch in großen Mengen produziert werden können.It is another object of the invention Process for the development or design of synthetic immunoglobulins to provide, which are produced in large quantities in milk can.
Die vorliegende Erfindung ermöglicht Verfahren zur Verabreichung therapeutisch vorteilhafter Antikörper an säugende Jungen, indem weibliche Säugetiere erzeugt werden, die solche Antikörper in ihrer Milch ausscheiden.The present invention enables methods for the administration of therapeutically advantageous antibodies suckling Boys by female mammals generated such antibodies excreted in their milk.
Die vorliegende Erfindung verwendet ein transgenes nicht-menschliches Säugetier mit Keim- und somatischen Zellen mit rekombinanten DNA-Sequenzen, die Leichte- und Schwere- Immunglobulin-Ketten kodieren, wobei die Sequenzen operativ an ihren 5'-Termini an einen säugetierspezifischen Promotor und an ihrem 3'-Ende an eine Sequenz gebunden sind, die eine Polyadenylierungsstelle umfasst.The present invention uses a transgenic non-human mammal with germ and somatic Cells with recombinant DNA sequences that are mild and severe Encode immunoglobulin chains, the sequences being operatively linked to theirs 5 'terms to one mammal specific Promoter and at its 3 'end are linked to a sequence that contains a polyadenylation site includes.
Die vorliegende Erfindung verwendet vorzugsweise eine Caseinpromotor-Kassette, die in 5'-nach 3'-Richtung folgendes umfasst:
- a) 5'-Promotorsequenzen aus dem beta-Caseingen,
- b) eine XhoI-Restriktionsstelle und
- c) 3' untranslatierte Sequenzen aus dem Ziegen-beta-Caseingen.
- a) 5 'promoter sequences from the beta-case gene,
- b) an XhoI restriction site and
- c) 3 'untranslated sequences from the goat beta case gene.
Kurze Beschreibung der ZeichnungenShort description of the drawings
Zusammenfassung der ErfindungSummary the invention
Diese Erfindung umfasst gemäß einem Aspekt ein Verfahren zur Gewinnung heterologer Immunglobuline aus der Milch transgener Säugetiere. Die vorliegende Erfindung schließt die Erzeugung transgener Säugetiere durch Einbringung von Immunglobulin-cDNA, gebunden an einen Milch-spezifischen Promotor, in ihre Keimbahn, ein.This invention comprises according to one Aspect of a method for obtaining heterologous immunoglobulins the milk of transgenic mammals. The present invention includes the generation of transgenic mammals by introducing immunoglobulin cDNA bound to a milk-specific Promoter, in their germline, a.
Solche transgenen Säugetiere weisen Keimzellen und somatische Zellen mit rekombinanten DNA-Sequenzen auf, die Immunglobulin cDNA gebunden an einen Milch-spezifischen Promotor umfassen.Such transgenic mammals exhibit germ cells and somatic cells with recombinant DNA sequences on, the immunoglobulin cDNA bound to a milk-specific Promoter include.
Die vorliegende Erfindung verwendet vorzugsweise eine isolierte DNA, die eine Expressionskassette mit 5'- und 3'-nicht-kodierenden Sequenzen umfasst, gewonnen aus dem Ziegen-Beta-Caseingen, gebunden über eine einzigartige Restriktionsstelle, die als geeignete Klonierungsstelle für die Immunglobulin kodierenden Sequenzen dient.The present invention uses preferably an isolated DNA containing an expression cassette 5 'and 3' non-coding Comprises sequences obtained from the goat beta-case gene, bound via a unique restriction site that acts as a suitable cloning site for the Serves sequences coding for immunoglobulin.
Ausführliche Beschreibung der ErfindungFull Description of the invention
Die vorliegende Erfindung stellt ein Verfahren zur Gewinnung eines heterologen und zusammengesetzten Immunglobulins aus der Milch nicht-humaner transgener Säugetiere bereit, dadurch gekennzeichnet, dass es folgendes umfasst:
- a) Einbringen von DNA in die Keimbahn des Säugetiers, die getrennt die Protein kodierenden Sequenzen der schweren und leichten Kette des Immunglobulins umfasst, wobei die DNA operativ an eine Ziegen-beta-Casein-Promotorsequenz, die die bevorzugte Expression der Protein kodierenden Sequenz in Brustdrüsenepithelzellen unterstützt, und an ihrem 3'-Terminus an eine Sequenz gebunden ist, die eine Polyadenylierungsstelle enthält;
- b) Gewinnen von Milch, die das heterologe und zusammengesetzte Immunglobulin enthält, aus dem nicht-menschlichen Säugetier;
wobei das heterologe und zusammengesetzte Immunglobulin in einer funktionellen Konfiguration vorliegt und in einer Konzentration von zumindest 1 mg/ml in der Milch des Säugetiers erzeugt wird.The present invention provides a method for obtaining a heterologous and composite immunoglobulin from the milk of non-human transgenic mammals, characterized in that it comprises:
- a) Introducing DNA into the mammalian germline, which separately comprises the protein coding sequences of the heavy and light chain of the immunoglobulin, the DNA being operably linked to a goat beta casein promoter sequence which expresses the preferred expression of the protein coding sequence in mammary epithelial cells supported, and at its 3 'terminus is linked to a sequence containing a polyadenylation site;
- b) obtaining milk containing the heterologous and composite immunoglobulin from the non-human mammal;
wherein the heterologous and composite immunoglobulin is in a functional configuration and is produced in a concentration of at least 1 mg / ml in the milk of the mammal.
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung monoklonaler Antikörper, die in die Milch von transgenen Tieren ausgeschieden werden und betrifft das Verfahren zur Herstellung solcher Tiere. Dies wird erreicht durch gentechnisches Verändern von DNA-Konstrukten, bei denen die DNA-Segmente, die getrennt spezifische gepaarte leichte und schwere Ketten eines Immunglobulins kodieren, stromabwärts einer Promotorsequenz kloniert werden, die vorzugsweise in Brustdrüsenepithelzellen exprimiert werden. Die rekombinanten DNAs, die die Promotor gebundenen Gene für die schwere und leichte Kette enthalten, werden dann in Präimplantations-Embryos coinjiziert. Die Nachkommenschaft wird auf das Vorhandensein beider Transgene gescreent. Repräsentative weibliche Tiere aus diesen Linien werden dann gemolken und die Milch wird auf das Vorhandensein des monoklonalen Antikörpers hin untersucht. Damit der Antikörper anwesend sein kann, müssen sowohl die Gene für die schwere Kette als auch die leichte Kette gleichzeitig in derselben Zelle exprimiert werden. Die Antikörper können aus der Milch aufgereinigt werden oder die Milch selbst, die die Immunglobuline umfasst, kann dazu verwendet werden, die Antikörper an einen Empfänger abzugeben bzw. zu liefern. Dies wird unten diskutiert.The present invention relates to a method for producing monoclonal antibodies which are excreted in the milk of transgenic animals and relates to the method for producing such animals. This is achieved through genetic engineering of DNA constructs in which the DNA segments that separately encode specific paired light and heavy chains of an immunoglobulin, cloned downstream of a promoter sequence, which are preferably expressed in mammary epithelial cells. The recombinant DNAs containing the promoter-bound heavy and light chain genes are then co-injected into pre-implantation embryos. The offspring is screened for the presence of both transgenes. Representative female animals from these lines are then milked and the milk is examined for the presence of the monoclonal antibody. For the antibody to be present, both the heavy chain and light chain genes must be expressed simultaneously in the same cell. The antibodies can be purified from the milk or the milk itself comprising the immunoglobulins can be used to deliver or deliver the antibodies to a recipient. This is discussed below.
Die in der vorliegenden Erfindung nützlichen Immunglobulingene können aus natürlichen Quellen gewonnen werden, beispielsweise individuellen B-Zellklonen oder Hybridomas, die hiervon abgeleitet sind. Darüber hinaus können rekombinante Antikörper-Gene verwendet werden, die durch Nukleotidsubstitutionen in vorhergesehener Weise verändert wurden, und die die Aminosäuresequenz durch Addition oder Deletion von Sequenzen oder durch Erzeugung von Hybridgenen ändern oder nicht ändern, bei denen unterschiedliche Regionen des Polypeptids aus unterschiedlichen Quellen abgeleitet sind. Antikörper-Gene sind ihrer Natur nach äußerst unterschiedlich und tolerieren somit natürlicherweise eine große Menge an Variationen. Es wird vom Fachmann auf dem Gebiet erkannt werden, dass die einzige Beschränkung zur Erzeugung eines Antikörpers durch das Verfahren der vorliegenden Erfindung darin besteht, dass er sich zu einer funktionellen Konfiguration zusammenfügen und in einer stabilen Form in die Milch sezerniert werden muss.Those in the present invention useful Immunoglobulin genes can from natural Sources are obtained, for example individual B cell clones or hybridomas derived therefrom. Furthermore can recombinant antibody genes used by nucleotide substitutions in predicted Way changed and the amino acid sequence by adding or deleting sequences or by generating of hybrid genes change or not change where different regions of the polypeptide come from different Sources are derived. Antibody genes are extremely different in nature and thus tolerate naturally a big Amount of variations. It is recognized by those skilled in the art that the only limitation to generate an antibody the method of the present invention is that it merge into a functional configuration and must be secreted into the milk in a stable form.
Die Transkriptionspromotoren, die in der Ausübung der vorliegenden Erfindung nützlich sind sind solche Promotoren, die in erster Linie in Brustdrüsenepithelzellen aktiviert werden, insbesondere der Promotor, der aus dem Ziegen-beta-Casein-Gen abgeleitet ist (DiTullio, (1992) Bio/Technology 10: 74–77).The transcription promoters that in the exercise of the present invention are those promoters that are primarily found in mammary epithelial cells be activated, especially the promoter coming from the goat beta casein gene is derived (DiTullio, (1992) Bio / Technology 10: 74-77).
Zur Verwendung in der vorliegenden Erfindung wird eine einzigartige bzw. einmal vorhandene XhoI Restriktionsstelle am 3'-Terminus der Promotorsequenz eingebracht, um eine Routine-Insertion der das Immunglobulin kodierenden Sequenzen zu ermöglichen. Vorzugsweise wird das eingefügte Immunglobulingen an seiner 3'-Seite von bekannten genomischen Sequenzen aus einem Brustdrüsen-spezifischen Gen flankiert, um eine Polyadenylierungsstelle und Transkript-stabilisierende Sequenzen bereitzustellen. Die Transkription des Konstruktes in vivo hat die Produktion einer stabilen mRNA zur Folge, die Casein-abgeleitete 5' untranslatierte Sequenzen stromaufwärts des Translationsinitiatorcodons des Immunglobulingenes und 3' untranslatierte Sequenzen stromabwärts des Translationsstopcodons des Immunglobulins enthalten. Zuletzt wird die gesamte Kassette (d. h. Promotor-Immunglobulin 3'-Region) durch Restriktionsstellen flankiert, die ermöglichen, dass die Promotor-cDNA-Kassette einfach aus einem einzelnen Fragment ausgeschnitten wird. Dies erleichtert die Entfernung un erwünschter prokaryontischer Vektor-abgeleiteter DNA-Sequenzen vor Injektion in befruchtete Eier.For Use In The Present Invention becomes a unique XhoI restriction site at the 3 'terminus of Promoter sequence introduced to a routine insertion of the immunoglobulin to enable coding sequences. Preferably the inserted one Immunoglobulins on its 3 'side of known genomic sequences from a mammary specific Gene flanked to a polyadenylation site and transcript stabilizing To provide sequences. The transcription of the construct in vivo results in the production of a stable mRNA, the casein-derived 5 'untranslated Sequences upstream of the translation initiator codon of the immunoglobulin gene and 3 'untranslated Sequences downstream of the translation stop codon of immunoglobulin. Last the entire cassette (i.e. promoter-immunoglobulin 3 'region) through restriction sites flanked that allow that the promoter cDNA cassette is simply a single fragment is cut out. This facilitates unwanted removal prokaryotic vector-derived DNA sequences before injection in fertilized eggs.
Die Promotor-gebundenen schwere und leichte Kette-DNAs des Immunglobulins werden dann in die Keimbahn eines Säugetiers eingebracht, beispielsweise einer Kuh, Schaf, Ziege, Maus, Ochsen, Kamel oder Schwein. Säugetiere sind hierin als alle Tiere, ausgenommen Menschen, definiert, die Brustdrüsen aufweisen und Milch erzeugen. Säugetierspezies, die Milch in großen Mengen über lange Zeitspannen produzieren werden bevorzugt. Typischerweise wird die DNA in die Pronuclei befruchteter Eier injiziert, die dann in den Uterus eines weiblichen Empfängertieres implantiert und ausgetragen werden. Nach der Geburt werden die vermeintlichen transgenen Tiere auf das Vorhandensein der eingebrachten DNA hin getestet. Dies wird in einfacher Weise durch eine Southern Blot-Hybridisierung der DNA erreicht, die aus Blutzellen oder anderen verfügbaren Geweben extrahiert wurde, unter Verwendung eines Segmentes des injizierten Gens als Sonde, das keine Kreuzhybridisierung mit der DNA der Empfängerspezies zeigt. Die Nachkommenschaft, die einen Beweis für zumindest eine Kopie der Gene für die schwere Kette und leichte Kette des Immunglobulins zeigt werden für eine weitere Analyse ausgewählt.The promoter-bound heavy and immunoglobulin light chain DNAs are then in the germline of a mammal introduced, for example a cow, sheep, goat, mouse, ox, Camel or pig. mammals are defined herein as all animals, excluding humans, that mammary glands have and produce milk. Mammalian species, the milk in large Amounts over producing long periods of time are preferred. Typically the DNA is injected into the pronuclei of fertilized eggs, which are then injected into the uterus of a female recipient animal be implanted and delivered. After the birth, the supposed transgenic animals for the presence of the introduced DNA tested. This is easily done by Southern blot hybridization the DNA reaches from blood cells or other available tissues was extracted using a segment of the injected Gens as a probe that does not cross hybridize with the DNA of the recipient species shows. The progeny who have proof of at least one copy of the Genes for the heavy chain and light chain of immunoglobulin are shown for one further analysis selected.
Transgene weibliche Tiere werden bzgl. ihrer Immunglobulinsekretion in Milch unter Verwendung irgendwelcher immunologischer Techniken, die in der Technik Standard sind (beispielsweise Western Blot, Radioimmunassay, ELISA), getestet. Die anti-Immunglobulin-Antikörper, die in dieser Analyse verwendet werden, können polyklonale oder monoklonale Antikörper sein, die isolierte schwere oder leichte Ketten nachweisen oder andere, die nur mit vollständig zusammengebauten (H2L2) Immunglobulinen reagieren.Become transgenic female animals for their immunoglobulin secretion in milk using any immunological techniques that are standard in the art (e.g. Western blot, radioimmunoassay, ELISA). The anti-immunoglobulin antibodies that Polyclonal or monoclonal can be used in this analysis antibody be able to demonstrate isolated heavy or light chains or others that only with complete assembled (H2L2) immunoglobulins react.
Die rekombinanten Immunglobuline werden ebenfalls bzgl. ihrer Funktionalität charakterisiert, d. h. ihrer Bindungsspezifität und Affinität für ein spezielles Antigen. Dies wird unter Verwendung immunologischer Verfahren erreicht, die in der Technik Standard sind, beispielsweise einer Scatchard-Analyse, Bindung an immobilisiertes Antigen etc. Die Stabilitätseigenschaften eines Immunglobulins in der Milch einer gegebenen Spezies werden ebenfalls untersucht, indem die oben beschriebenen Nachweisverfahren auf Milch angewendet werden, die für zunehmende Zeitspannen nach Gewinnung aus dem Tier inkubiert werden.The recombinant immunoglobulins are also characterized in terms of their functionality, i. H. of their binding specificity and affinity for a special antigen. This is done using immunological methods achieved that are standard in technology, for example one Scatchard analysis, binding to immobilized antigen etc. The stability properties of an immunoglobulin in the milk of a given species also examined using the detection methods described above be applied to milk after increasing periods of time Extraction can be incubated from the animal.
Die durch die Verfahren der vorliegenden Erfindung produzierten Immunglobuline können aus Milch unter Verwendung einer Absorption an immobilisiertes Protein G, Säulenchromatographie, und unter Verwendung anderer Verfahren aufgereinigt werden, die dem Durchschnittsfachmann auf dem Gebiet der Antikörperaufreinigung bekannt sind.The immunoglobulins produced by the methods of the present invention can be obtained from milk using an immobilized protein G absorption, column chromatography, and using other methods known to those of ordinary skill in the antibody purification art are purified.
Die Produktionskonzentration bzw. -niveaus rekombinanter Immunglobuline in einem individuellen transgenen Tier werden in erster Linie durch den Ort und die Art und Weise des Einbaus des Transgens nach Injektion in das befruchtete Ei bestimmt. Somit kann die transgene Nachkommenschaft, die aus unterschiedlichen injizierten Eiern abgeleitet ist, bezüglich dieses Parameters variieren. Die Menge an rekombinantem Immunglobulin in der Milch wird deswegen in der repräsentativen Nachkommenschaft überwacht und die am höchsten produzierenden weiblichen Tiere werden bevorzugt.The production concentration or levels of recombinant immunoglobulins in an individual transgenic Animal are made primarily by the place and the way the incorporation of the transgene after injection into the fertilized egg. Thus, the transgenic progeny that come from different injected eggs is derived, vary with this parameter. The amount of recombinant immunoglobulin in milk therefore becomes in the representative Offspring monitored and the highest producing female animals are preferred.
Der Fachmann auf dem Gebiet wird erkennen, dass die Verfahren der vorliegenden Erfindung dazu verwendet werden können, die Produktion natürlicher und synthetischer Immunglobuline zu optimieren. Die Schritte der Erzeugung eines transgenen Tieres, das Testen auf das Vorhandensein von Genen sowohl für die schweren als auch leichten Ketten-Gene, eine Untersuchung der Sekretion von Immunglobulin in die Milch der weiblichen Nachkommenschaft und letztendlich der Qualität der sich ergebenden Antikörper kann sequentiell ohne unzumutbare Experimente wiederholt werden, um bevorzugte Konstrukte für unterschiedliche Anwendungen zu etablieren.The person skilled in the art will recognize that the methods of the present invention are used for this can be the production more natural and to optimize synthetic immunoglobulins. The steps of the Generation of a transgenic animal, testing for presence of genes for both the heavy as well as light chain genes, an investigation of the Secretion of immunoglobulin in the milk of female offspring and ultimately quality the resulting antibody can be repeated sequentially without undue experimentation, to preferred constructs for to establish different applications.
Gemäß der vorliegenden Erfindung kann die Art der rekombinanten Immunglobuline und ihre spezielle Anwendungsweise variieren. In einer Ausführungsform umfasst die vorliegende Erfindung die Expression von Antikörpern auf hohem Niveau, die aus Milch gewonnen und aufgereinigt und in gereinigter Form verwendet werden. Die Expression auf hohem Niveau ist hierin als die Produktion von ungefähr 1 mg/ml Protein definiert. Alternativ sind die Antikörper gentechnisch verändert, so dass ein Schutz von Menschen gegen Infektionskrankheiten bereitgestellt wird; die therapeutische Verabreichung wird dann durch Trinken der Milch erzielt. Bei einer weiteren Möglichkeit werden milchgebende Tiere so gentechnisch verändert, dass sie Antikörper produzieren, die für ihre Nachkommenschaft besonders von Vorteil sind und die diese durch Säugen aufnehmen. Bei einer noch weiteren Möglichkeit erzeugen Tiere einen Antikörper, den das milchgebende Säugetier selbst gegen Brustdrüsenpathogene schützt, beispielsweise Bakterien, die eine Mastitis erzeugen.According to the present invention can be the type of recombinant immunoglobulins and their specific application vary. In one embodiment the present invention includes expression of antibodies high level, obtained from milk and purified and cleaned Shape can be used. The high level expression is here than the production of about 1 mg / ml protein defined. Alternatively, the antibodies are genetic changed providing protection against infectious diseases becomes; the therapeutic administration is then by drinking the Milk obtained. Another option is to give milk Animals so genetically engineered that they have antibodies produce that for their offspring are particularly beneficial and are brought about by them Suckle take up. In yet another way, animals create one Antibody, the milk-giving mammal even against mammary pathogens protects for example bacteria that cause mastitis.
Die unerwartet hochvolumige Expression von Immunglobulinen gemäß der vorliegenden Erfindung ermöglicht ebenfalls die Verwendung solcher Immunglobuline in pharmazeutischen und chemischen Einrichtungen. Auf dem Wege eines nicht einschränkenden Beispiels kann das Verfahren der vorliegenden Erfindung dazu verwendet werden, hohe Mengen bzw. Konzentrationen an tetrameren Antikörpern zu erzeugen, die gegen verschiedene Pathogene gerichtet sind (beispielsweise E. coli, Salmonella, Hepatitis B Virus), biologisch aktive Peptide (beispielsweise Erythropoietin, Gewebsplasminogenaktivator, gamma-Interferon) und zur Verwendung in chemischen Reaktionen, die gegen verschiedene Enzyme gerichtet sind. Monoklonale Antikörper, die an den Übergangszustand einer chemischen Reaktion binden, können in der Produktion im industriellen Maßstab verwendet werden. Darüber hinaus werden monoklonale Antikörper oftmals an Säulen zur Verwendung in der Aufreinigung von biopharmazeutischen Mitteln immobilisiert; in solchen Fällen repräsentiert die Produktion der Antikörper eine signifikante Fraktion der Aufreinigungskosten. Die Verfahren der vorliegenden Erfindung ermöglichen die Produktion von hochvolumigen Antikörpervorräten mit geringen Kosten zur Verwendung in diesen Anwendungstypen.The unexpectedly high volume expression of immunoglobulins according to the present Invention enables also the use of such immunoglobulins in pharmaceutical and chemical facilities. On the way of a non-restrictive For example, the method of the present invention can be used for this are high amounts or concentrations of tetrameric antibodies generate that are directed against different pathogens (for example E. coli, Salmonella, hepatitis B virus), biologically active peptides (e.g. erythropoietin, tissue plasminogen activator, gamma interferon) and for use in chemical reactions against various Enzymes are directed. Monoclonal antibodies linked to the transition state chemical reaction can be used in production on an industrial scale become. About that In addition, monoclonal antibodies often on pillars for use in the purification of biopharmaceuticals immobilized; in such cases represents the production of the antibodies a significant fraction of the purification costs. The proceedings enable the present invention the production of high volume antibody stocks at low cost Use in these types of applications.
Die vorliegende Erfindung wird weiterhin in den nachfolgenden Arbeitsbeispielen beschrieben.The present invention will continue described in the following working examples.
Beispiel 1: Konstruktion einer milchspezifischen Promotor-KassetteExample 1: Construction a milk-specific promoter cassette
Die vorliegende Erfindung umfasst einen Rezipientenvektor, in den viele unterschiedliche Immunglobulingene in austauschbarer Weise eingefügt werden können. Der Vektor enthält 5' milchspezifische Promotorsequenzen und 3' untranslatierte genomische Sequenzen, die eine XhoI Klonierungsstelle flankieren. Diese Klonierung ist einmalig, weil sie die einzige im Vektor vorliegende ist. Vorzugsweise sollte die gesamte Expressionskassette durch Restriktionsstellen, die den einfachen Ausschnitt bzw. Exzision der Promotor-gebundenen Immunglobulingene ermöglichen.The present invention encompasses a recipient vector in which many different immunoglobulin genes inserted in an interchangeable manner can be. The vector contains 5 'milk specific Promoter sequences and 3 'untranslated genomic sequences flanking an XhoI cloning site. This cloning is unique because it is the only one present in the vector is. The entire expression cassette should preferably be restricted by restriction sites, the simple cutout or excision of the promoter-bound immunoglobulin genes enable.
In diesem Beispiel wurden die Promotor- und 3' genomischen Sequenzen aus dem Ziegenbeta-Casein-Gen gewonnen. Das Gen wurde kloniert und wie von Roberts et al., 1992, Gene 121: 255–262 beschrieben charakterisiert.In this example, the promoter and 3 'genomic Sequences obtained from the goat beta casein gene. The gene was cloned and characterized as described by Roberts et al., 1992, Gene 121: 255-262.
Die Expressionskassette besteht vor der Einfügung der Immunglobulingene aus 6,2 kb stromaufwärts des Translationsstartes der beta-Casein kodierenden Sequenz und 7,1 kb der genomischen Sequenz stromabwärts des Translationsstops des beta-Casein-Gens. Die TagI-Stelle gerade stromaufwärts des Translationsstartcodons wurde durch eine XhoI-Stelle vertauscht. Diese einmal vorkommende XhoI-Klonierungsstelle liegt an der Kreuzung der stromaufwärts und stromabwärts gelegenen Sequenzen vor. Es ist diese XhoI-Stelle, enthalten in der Sequenz CGCGGATCCTCGAGGAC, in die rekombinante Immunglobulingene eingefügt werden (D. Tullio, (1992) Bio/Technology 10: 74–77).The expression cassette is available the insertion the 6.2 kb immunoglobulin genes upstream of the translation start the beta-casein coding sequence and 7.1 kb of the genomic sequence downstream the translation stop of the beta-casein gene. The TagI position straight upstream of the translation start codon was exchanged for an XhoI site. This unique XhoI cloning site is at the intersection the upstream and downstream sequences. It is this XhoI site contained in the sequence CGCGGATCCTCGAGGAC, into the recombinant immunoglobulin genes added (D. Tullio, (1992) Bio / Technology 10: 74-77).
Die 3' Beta-Casein-Region beginnt an der PpuMI-Stelle, die in Exon 7 zu finden ist und dauert für 7,1 kb stromabwärts an. Eingeschlossen in diese Sequenz sind die übrigen 18 bp von Exon 7 und das gesamte Exon 8 und Exon 9. Diese kodieren die 3' untranslatierten Regionen des Ziegen-beta-Casein-Gens und enden mit der Sequenz: TAAGGTCCACAGACCGAGACC-CACTCACTAGGCAACTGGTCCGTCCAGCTGTTAAGTGA.The 3 'beta casein region begins at the PpuMI site found in exon 7 and continues downstream for 7.1 kb. Included in this sequence are the remaining 18 bp of exon 7 and the entire one Exon 8 and Exon 9. These encode the 3 'untranslated regions of the goat beta casein gene and end with the sequence: TAAGGTCCACAGACCGAGACC-CACTCACTAGGCAACTGGTCCGTCCAGCTGTTAAGTGA.
Um Restriktionsstellen gentechnisch einzufügen, die die Casein-Kassette flankieren, wurden die Ziegen beta-Casein-Kontrollsequenzen zunächst in den SuperCosI-Vektor kloniert (# 251301, Stratagene, La Jolla, CA) mit flankierenden NotI- und SalI-Stellen. Dieses Plasmid wurde dann durch Austauschen der NotI-Stelle durch eine SalI-Stelle verändert. Dies erzeugte ein 13,3 kb SalI-Fragment, das die beta-Casein-Expressionskassette im gbc163-Vektor enthielt.Genetically engineered around restriction sites insert, that flanked the casein cassette, the goats became beta-casein control sequences first cloned into the SuperCosI vector (# 251301, Stratagene, La Jolla, CA) with accompanying NotI and SalI positions. This plasmid was then changed by replacing the NotI point with a SalI point. This generated a 13.3 kb SalI fragment that contained the beta-casein expression cassette in gbc163 vector contained.
Beispiel 2: Konstruktion von Promotor-gebundenen monoklonalen Antikörper-GenenExample 2: Construction of promoter-bound monoclonal antibody genes
In diesem Beispiel wurden die Gene, die einen humanen monoklonalen Antikörper kodieren, die gegen eine Colon-Kebszell-Oberflächenmarker gerichtet waren, an den Casein-Promotor gebunden. cDNAs, die die leichten und schweren Ketten dieses Antikörpers kodieren wurden aus einer Antikörper-sezernierenden Hybridomzelllinie in eine pUC19-abgeleiteten Vektor kloniert. Die leichte und schwere Kette cDNA war auf HindIII/EcoRI-Fragmenten von 702 bp bzw. 1.416 bp vorhanden.In this example, the genes encoding a human monoclonal antibody against an Colon Kebszell surface marker were bound to the casein promoter. cDNAs that are light and heavy chains of this antibody were encoding from an antibody-secreting Hybridoma cell line cloned into a pUC19-derived vector. The light and heavy chain cDNA was on HindIII / EcoRI fragments of 702 bp or 1,416 bp available.
Um die Gene zur Einfügung in die Casein-Promotorkassette anzupassen wurden die XhoI-Restriktionsstellen an beiden Enden jedes DNA-Segments wie unten ausführlich beschrieben wird, gentechnisch verändert. Im selben Schritt wurde die Region stromaufwärts des Immunglobulintranslationsstartkodons so modifiziert, dass sie Sequenzen enthielt, die denjenigen in der analogen Region des beta-Casein-Gens ähnlich war.To insert the genes in The XhoI restriction sites were adapted to match the casein promoter cassette at both ends of each DNA segment as detailed below is genetically modified. In the same step, the region became upstream of the immunoglobulin translation start codon modified to contain sequences similar to those in the analogous region of the beta casein gene was similar.
Leichte Kette-Gen: Das pUC19-Plasmid, das den leichte Kette cDNA-Insert enthielt, wurde mit HindIII digeriert, durch Behandlung mit dem Klenow-Fragment durch DNA-Polymerase I mit stumpfen Enden versehen (blunt-ended) und an ein Oligonukleotid ligiert, das die XhoI-Erkennungssequenz enthielt (# 1030, New England Biolabs, Beverly, MA).Light chain gene: the pUC19 plasmid, which contained the light chain cDNA insert was digested with HindIII, by treatment with the Klenow fragment by DNA polymerase I provided with blunt ends and to an oligonucleotide that ligates the XhoI recognition sequence included (# 1030, New England Biolabs, Beverly, MA).
Die Region, die zum Start-ATG unmittelbar
stromaufwärts
lag wurde dann unter Verwendung eines Oligonukleotids mutagenisiert,
das die folgende Sequenz aufwies:
5' AGT GAA TTC ATG CTC GAG AGC CAT GGC
CTG GATC 3'The region immediately upstream of the start ATG was then mutagenized using an oligonucleotide that had the following sequence:
5 'AGT GAA TTC ATG CTC GAG AGC CAT GGC CTG GATC 3'
Die Digestion des endgültigen Plasmides mit XhoI erzeugte die modifizierte cDNA der leichtenKette, die von cohäsiven XhoI-Enden flankiert war.Digestion of the final plasmid with XhoI, the modified light chain cDNA generated by cohesive XhoI ends was flanked.
Die leichte Kette-cDNA wurde in die
einmal vorkommende XhoI-Klonierungsstelle des gbc163-Expressionsvektors
eingefügt,
der in Beispiel 1 beschrieben war, wodurch Plasmid Bc62 gewonnen
wurde (
Schwere Kette-Gen: Das pUC19-Plasmid,
das die Schwere Kette-cDNA enthielt wurde unter Verwendung eines
Oligonukleotids mit der folgenden Sequenz mutagenisiert:
5' AGT GAA TTC ATG
CTC GAG AGC CAT GAA GCA CCTG 3'Heavy chain gene: The pUC19 plasmid containing the heavy chain cDNA was mutagenized using an oligonucleotide with the following sequence:
5 'AGT GAA TTC ATG CTC GAG AGC CAT GAA GCA CCTG 3'
Das sich ergebende Plasmid enthält eine XhoI-Stelle stromaufwärts des schwere Kette-Translationsstartcodons.The resulting plasmid contains one XhoI site upstream of the heavy chain translation start codon.
Die stromabwärts gelegene HindIII-Stelle
wurde unter Verwendung eines Syntheseadapters mit der Sequenz 5' AGC TCC TCG AGG
CC 3' zu einer Xhol-Stelle
umgewandelt. Die Digestion des modifizierten Plasmids mit XhoI erzeugte
die 1,4 kb modifizierte schwere Kette-cDNA flankiert durch XhoI cohäsive Enden. Dieses
Fragment wurde dann in die einmal vorkommende XhoI-Klonierungsstelle
von gbc163 eingefügt,
um Bc61 zu erhalten (
Vor der Injektion wurden die Promotor-gebundenen leichten und schweren Ketten-Gene aus Bc61 bzw. Bc62 durch Digestion mit SalI isoliert. Die Fragmente wurden dann durch Gelelektrophorese gefolgt von CsCl Gleichgewichtsgradienten-Zentrifugation aufgereinigt. Die DNA wurde umfangreich gegen destilliertes Wasser vor der Quantifizierung dialysiert.Before the injection, the promoter was bound light and heavy chain genes from Bc61 or Bc62 by digestion isolated with SalI. The fragments were then by gel electrophoresis followed by CsCl equilibrium gradient centrifugation. The DNA became extensive against distilled water before quantification dialyzed.
Beispiel 3: Produktion transgener MäuseExample 3: Production transgenic mice
Die Caseinpromotor-gebundenen DNA-Fragmente, die die schweren und leichten Ketten des Immunglobulins kodieren, und die wie in Beispiel 2 beschrieben erzielt wurden, wurden in befruchtete Maus-Eier unter Verwendung von Verfahren injiziert, die in der Technik Standard sind, wie in Hogan, B., Constantini, F., und Lacey, E., Manipulating the Mouse Embryo: A Laboratory Manual (Cold Spring Harbor Laboratories, 1986) beschrieben, injiziert. Die sich ergebende Nachkommenschaft wurde dann auf das Vorhandensein beider Antikörpergen-Sequenzen untersucht. DNA wurde aus einem Schwanz-Biopsie-Material extrahiert und unter Verwendung einer Southern Blot-Analyse sondiert. Die Sonden, die in der Hybridisierung verwendet wurden, waren die Original-cDNAs, die die schwere und leichte Kette kodieren. Wie in Tabelle 1 ersichtlich ist, wies der größte Teil der ersten Generation der transgenen Nachkommenschaft beide Transgene auf.The casein promoter-bound DNA fragments, encoding the heavy and light chains of immunoglobulin, and which were achieved as described in Example 2 were in fertilized mouse eggs injected using procedures, which are standard in technology, as in Hogan, B., Constantini, F., and Lacey, E., Manipulating the Mouse Embryo: A Laboratory Manual (Cold Spring Harbor Laboratories, 1986). The resulting offspring was then checked for existence both antibody gene sequences examined. DNA was extracted from a tail biopsy material and under Using a Southern blot analysis probed. The probes that used in the hybridization were the original cDNAs, that encode the heavy and light chain. As can be seen in Table 1 is pointed out the most the first generation of the transgenic progeny both transgenes on.
Tabelle
1
Zusammenfassung von Bc61–Bc62
Mäusen 
Beispiel 4: Analyse der rekombinanten Immunglobuline in der MilchExample 4: Analysis of recombinant immunoglobulins in milk
Milchproben aus den wie in Beispiel
3 beschrieben gewonnenen transgenen Mäusen wurden auf das Vorhandensein
des heterologen Immunglobulins durch Western Blot untersucht. Die
schwere Kette des Antikörpers
wurde unter Verwendung eines Meerettichperoxidasegebundenen polyklonalen
Antikörpers
nachgewiesen, der gegen humane gamma-schwere Ketten gerichtet war
(Antikörper
# 62-8420), Zymed, South San Francisco, CA), wie in
Claims (4)
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| US170579 | 1993-12-20 | ||
| US08/170,579 US5827690A (en) | 1993-12-20 | 1993-12-20 | Transgenic production of antibodies in milk |
| PCT/US1994/014795 WO1995017085A1 (en) | 1993-12-20 | 1994-12-20 | Transgenic production of antibodies in milk |
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| EP (2) | EP0741515B1 (en) |
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| DE122007000007I1 (en) | 1986-04-09 | 2007-05-16 | Genzyme Corp | Genetically transformed animals secreting a desired protein in milk |
| US6657103B1 (en) | 1990-01-12 | 2003-12-02 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
| US6057287A (en) | 1994-01-11 | 2000-05-02 | Dyax Corp. | Kallikrein-binding "Kunitz domain" proteins and analogues thereof |
| GB9406974D0 (en) | 1994-04-08 | 1994-06-01 | Pharmaceutical Proteins Ltd | Transgenic production |
| WO1998037224A1 (en) * | 1997-02-25 | 1998-08-27 | Genzyme Transgenics Corporation | Transgenically produced non-secreted proteins |
| US6011197A (en) | 1997-03-06 | 2000-01-04 | Infigen, Inc. | Method of cloning bovines using reprogrammed non-embryonic bovine cells |
| JP2001520041A (en) | 1997-10-20 | 2001-10-30 | ジェンザイム トランスジェニックス コーポレイション | Novel modified nucleic acid sequences and methods for increasing mRNA levels and protein expression in cellular systems |
| EP0921189B1 (en) * | 1997-11-14 | 2005-01-12 | Sankyo Company Limited | Transgenic animal allergy models and methods for their use |
| US7790856B2 (en) | 1998-04-07 | 2010-09-07 | Janssen Alzheimer Immunotherapy | Humanized antibodies that recognize beta amyloid peptide |
| US7964192B1 (en) | 1997-12-02 | 2011-06-21 | Janssen Alzheimer Immunotherapy | Prevention and treatment of amyloidgenic disease |
| US7179892B2 (en) | 2000-12-06 | 2007-02-20 | Neuralab Limited | Humanized antibodies that recognize beta amyloid peptide |
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- 1994-12-20 NZ NZ278744A patent/NZ278744A/en not_active IP Right Cessation
- 1994-12-20 DE DE69433325T patent/DE69433325T2/en not_active Expired - Lifetime
- 1994-12-20 PT PT95906691T patent/PT741515E/en unknown
- 1994-12-20 EP EP95906691A patent/EP0741515B1/en not_active Expired - Lifetime
- 1994-12-20 AU AU15172/95A patent/AU688845B2/en not_active Ceased
- 1994-12-20 AT AT95906691T patent/ATE253817T1/en not_active IP Right Cessation
- 1994-12-20 JP JP51760295A patent/JP3970923B2/en not_active Expired - Lifetime
- 1994-12-20 WO PCT/US1994/014795 patent/WO1995017085A1/en active IP Right Grant
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- 1994-12-20 DK DK95906691T patent/DK0741515T3/en active
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- 1998-01-23 US US09/012,904 patent/US20040006776A1/en not_active Abandoned
- 1998-06-19 AU AU73079/98A patent/AU7307998A/en not_active Abandoned
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| AU688845B2 (en) | 1998-03-19 |
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| NZ278744A (en) | 1997-04-24 |
| US20040006776A1 (en) | 2004-01-08 |
| EP0741515A1 (en) | 1996-11-13 |
| US5827690A (en) | 1998-10-27 |
| AU7307998A (en) | 1998-08-20 |
| CA2178941A1 (en) | 1995-06-29 |
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